Primary pulmonary hypertension (PPH), a rapidly progressive and usually fatal disease, has an incidence rate among the HIV infected population many times higher than in the general population. Unfortunately, the pathogenesis of HIV-related pulmonary hypertension (HRPH) is not well understood. Nevertheless, the histological similarities are striking: uncontrolled endothelial cell (EC) proliferation and formation of plexogenic lesions obliterate the Lumina of the pulmonary arteries with subsequent right heart failure. The immune dysregulation, chronic exposure to viral products in the lung and altered chemokine/cytokine profile may contribute to the injury. In the lung, HIV-1 infects primarily macrophages providing a potential reservoir of virus and a source of localized viral proteins such as Nef, which can circulate and affect surrounding cells. Studies of HRPH have been hampered by lack of a suitable animal model. Since numerous primate models of HIV-1 recapitulate the immune deficiencies and complications seen in humans, we undertook a study of lungs from macaques infected with an SIV/HIV chimeric virus containing HIV-1 Nef (SHIVnefSF33A) and found plexogenic lesions in the lungs of SHIV-nef but not in SIV Nef-infected macaques, suggesting that there are functional differences between the nef alleles in their ability to promote pulmonary vascular remodeling. We propose to study the natural history and progression of HRPH in SHIVnef infected monkeys. Our specific hypothesis is that immune dysregulation of SHIVnef-infected monkeys, triggers a phenotypic switch in EC that allows selection of a highly proliferative, growth-dysregulated EC population that obliterates the Lumina of pulmonary arteries through plexiform lesion formation. To study this, we will address the following question: What is the natural history of PH in macaques infected with SHIVnef, and in a background of gammaherpesvirus infection? We will infect the monkeys, track PH development post-infection, and will correlate immunological parameters with lesion formation. Does HIV nef lead to the acquisition of a proliferative phenotype in lung microvascular EC? We will examine the in vitro proliferative properties of pulmonary endothelial cells after exposure to various nef alleles/mutants or to conditioned media from macrophages exposed to these as well. Using a primate model system that is phylogenetically very close to humans allows us to study both the initiation and progression phases of HRPH.